Therapeutic treatments for solid tumors usually include a combination of DNA damaging agents, including a class of compounds that are metabolized by the CYP3A4 protein. These DNA damaging agents include topoisomerase inhibitors, and doxorubicin or adriamycin, which is an anthracycline antibiotic that is frequently used in combination with other drugs for treating breast cancer. Doxorubicin acts through multiple mechanisms that include intercalating within DNA, binding to topoisomerase II, and generating reactive oxygen species. The effectiveness of doxorubicin- or topoisomerase inhibitor-based chemotherapy is limited by drug resistance. For example, doxorubicin resistance can emerge through alterations of proteins regulating the availability, activation, or inactivation of the drug, through changes in topoisomerase II, or through changes in pathways mediating DNA repair and apoptosis. The proteins that cause chemotherapeutic resistance are potential therapeutic targets for cancer, and inhibiting these proteins could lead to improved effectiveness of doxorubicin and other compounds that are metabolized by Cyp3A4.
Hpr6 is a member of the heme-1 domain family of proteins, which includes the human Hpr6 and Dg6 proteins, the rodent 25-Dx and IZAg proteins, and the budding yeast Dap1p protein. The Hpr6/25-Dx/IZAg/Dap1p proteins are relatively small (approximately 25 kDa) and are composed largely of a central heme-1 domain that shares homology with cytochrome b5. Like cytochrome b5, the IZAg protein binds to heme. Dap 1 p damage resistance protein, 7) was previously identified in Saccharomyces cerevisiae, a model organism for studying chemotherapeutic resistance. Yeast mutants lacking Dap 1 p exhibit extreme sensitivity to a DNA alkylating agent and are moderately sensitive to hydroxyurea and radiation (Hand R A et al., Eukaryotic Cell 2003; 2: 121-32).
Thus, drugs that target the Hpr6 protein are potentially useful for treating cancer. Drug resistance is one of the primary causes underlying failure of treatment for cancer, and there is a profound need to screen for inhibitors of the Hpr6 pathway.